Role of the human gut microbiome and related metabolites for causally mediating vascular endothelial function

人类肠道微生物组和相关代谢物在因果介导血管内皮功能中的作用

基本信息

批准号：
10794927
负责人：
Abigail Grace Longtine
金额：
$ 2.57万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10794927
关键词：
Acetylcholine Address Adult Age Aging Antioxidants Aorta Arteries Biochemical Biological Biological Assay Biological Availability Biological Process Blood Vessels Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cause of Death Cell Culture Techniques Cell Separation Cells Circulation Clinical Trials Colorado Data Development Disease Dissection Education Elderly Endothelial Cells Endothelium Exposure to Fellowship Funding Future Human Human Microbiome Impairment International Laboratories Learning Link Measures Mediating Mentors Metabolic Mus NG-Nitroarginine Methyl Ester National Heart, Lung, and Blood Institute Nitric Oxide Nitric Oxide Synthetase Inhibitor Organism Oxidative Stress Physiological Physiology Plasma Prevention Process Production Recording of previous events Research Research Personnel Research Priority Research Project Grants Role Scientist Strategic vision Superoxide Dismutase Superoxides Supervision Techniques Tissues Training Translations Transplantation Umbilical vein United States National Institutes of Health Universities Vascular Endothelial Cell Vascular Endothelium Woman age effect age related cardiovascular disorder risk cardiovascular risk factor circulating plasma factor clinical application doctoral student endothelial dysfunction experience experimental study fecal transplantation gut microbiome gut microbiota human microbiota humanized mouse improved innovation insight men metabolomics microbial microbiome composition microbiota mimetics mouse model new therapeutic target novel pre-clinical prevent response seal skills small molecule tempol therapeutic target translational approach vascular endothelial dysfunction young adult

项目摘要

PROJECT SUMMARY/ABSTRACT The purpose of this F31 application is to provide support for Ms. Abigail Casso, a 2nd year PhD student in Dr. Douglas Seals’ (sponsor) laboratory at the University of Colorado Boulder, to conduct research and training that will prepare her to become an independent investigator in the field of translational cardiovascular (CV) aging research aimed at the prevention and treatment of age-related CV diseases (CVD). As part of her proposed training plan, she aims to both refine research skills presently under development and learn a variety of new technical, conceptual, and professional skills, including the use of preclinical mouse models and gaining new experiences using human biospecimens, cell culture bioassays, and metabolomics approaches. Her proposed research project seeks to investigate the role of age-related changes in the human gut microbiome and circulating gut microbiome-derived metabolites in impairing vascular endothelial function. Gut microbiome composition is uniquely altered with CVD and aging, and age-related changes in circulating concentrations of certain gut-derived metabolites have been related to CVD. However, whether these age-related changes causally impair endothelial function is unknown. Guided by strong preliminary data, Ms. Casso will determine: (Aim 1) If age-related changes in the human gut microbiome impair endothelial function due to increased oxidative stress and reduced nitric oxide bioavailability using innovative “humanized” mouse models and ex vivo “pharmaco-dissection” techniques; (Aim 2A) The effect of age-related, gut microbiome-induced changes in plasma circulating factors on endothelial function using cell culture bioassays; (Aim 2B) Which circulating metabolites are altered by the aging human gut microbiome via targeted metabolomics; and (Aim 3) If specific gut-derived metabolites that are increased in circulation with age directly induce endothelial dysfunction using cell culture and isolated vessel approaches. The expected results will identify novel gut microbiome-related and circulating gut-derived metabolite modulators of endothelial function and may facilitate translation of these metabolites as new therapeutic targets for prevention and treatment of age-related endothelial dysfunction. Overall, the proposed research has the potential to address important NHLBI Strategic Vision research priorities, including: 1) investigate new pathobiological mechanisms important to the onset of CVD; and 2) identify novel therapeutic targets to prevent and treat CVD113. Dr. Seals is an internationally recognized and NIH-funded scientist with a strong history of successful mentoring in translational CV research, particularly in the emerging field of “vascular aging”. Under his supervision and with the guidance of content expert co- mentors Drs. Vienna Brunt, Angelo D’Alessandro, and Tiffany Weir, Ms. Casso will be able to successfully complete the proposed research and training plan, facilitating her ongoing development towards becoming an independent investigator in mechanistic and translational CV aging research.

项目概要/摘要此 F31 申请的目的是为 Dr. Dr. 的二年级博士生 Abigail Casso 女士提供支持。科罗拉多大学博尔德分校的道格拉斯·西尔斯（赞助商）实验室进行研究和培训这将使她做好成为转化心血管（CV）领域的独立研究者的准备衰老研究旨在预防和治疗与年龄相关的心血管疾病（CVD）。根据拟议的培训计划，她的目标是提高目前正在开发的研究技能并学习各种新技术、概念和专业技能，包括临床前小鼠模型的使用和获得使用人类生物样本、细胞培养生物测定和代谢组学方法的新体验。拟议的研究项目旨在调查人类肠道微生物组中与年龄相关的变化的作用和循环肠道微生物组衍生的代谢物损害血管内皮功能。其成分随着CVD和衰老而发生独特的改变，并且循环浓度与年龄相关的变化某些肠道来源的代谢物与 CVD 相关，但这些变化是否与年龄相关。内皮功能的致病性损害尚不清楚，在强有力的初步数据指导下，Casso 女士将确定：（目标 1）如果人类肠道微生物组中与年龄相关的变化由于增加而损害内皮功能使用创新的“人性化”小鼠模型和前体来减少氧化应激和减少一氧化氮生物利用度体内“药物解剖”技术；（目标 2A）年龄相关的肠道微生物组诱导的变化的影响使用细胞培养生物测定法检测血浆循环因素对内皮功能的影响（目标 2B）衰老的人类肠道微生物组通过靶向代谢组学改变代谢物；以及（目标 3）如果具体的话随着年龄的增长，循环中肠道来源的代谢物增加，直接诱导内皮功能障碍细胞培养和分离血管方法的预期结果将鉴定新的肠道微生物组相关的。和循环内皮功能的肠源性代谢调节剂，并可能促进这些物质的翻译代谢物作为预防和治疗年龄相关内皮功能障碍的新治疗靶点。总体而言，拟议的研究有可能解决重要的 NHLBI 战略愿景研究优先事项，包括：1) 研究对 CVD 发病重要的新病理生物学机制；2) Seals 博士是国际公认的识别预防和治疗 CVD113 的新治疗靶点的科学家。美国国立卫生研究院 (NIH) 资助的科学家，在转化型简历研究方面拥有成功指导的悠久历史，特别是在在他的监督和内容专家的指导下，“血管老化”这个新兴领域。导师Vienna Brunt博士、Angelo D’Alessandro博士和Tiffany Weir博士、Casso女士将能够成功完成拟议的研究和培训计划，促进她不断发展成为一名机械和转化CV老化研究的独立研究者。